During acute inflammatory reactions, leukocytes and serum molecules are relocated to areas of damage in the body. These areas of damage are often associated with physical injury. Upon injury, the clotting system and plasmin systems are initiated together with the appropriate nervous system response to generate an initial response to facilitate immune activation. Increased blood flow, capillary permeability and chemotactic factors, including those of the complement cascade, modulate neutrophil migration to the damaged site. Neutrophils are the predominant cell type involved in acute inflammation, whereas lymphocytes and macrophages are more prevalent in chronic inflammation.
Cytokines are proteins from inflammatory and parenchymal cells that regulate the immune response. T cells, macrophages, and B cells all produce and respond to the appropriate cytokines. Neutrophils are also activated in response to cytokines. While activation of the appropriate inflammatory pathways is necessary for an effective inflammatory response, there can also be negative aspects to cytokine-mediated cell activation.
Two cytokines, TNF (tumor necrosis factor) and IL-1 (Interleukin-1) upregulate the acute inflammatory pathway. These molecules influence cell migration as well as many of the pathophysiologic responses associated with the acute inflammatory reaction. IL-1 and TNF, together with other cytokines, can also induce systemic effects including neutrophilia, lymphopenia, fever, and hypotensive shock.
Gram-negative bacteria have a proinflammatory lipopolysaccharide component (LPS) of their cell walls that is a potent endotoxin. Activation of acute inflammation in response to the endotoxin, LPS, is primarily orchestrated by cytokines. This endotoxin upregulates IL-1 and TNF. Over-activation of the acute inflammatory response via IL-1 and TNF can lead to negative local effects such as abscess formation with irreversible parenchymal damage and sometimes life-threatening systemic side effects such as hypotensive shock.
Over-expression of TNF and IL-1 produces a shock syndrome as observed when pure TNF or IL-1 are administered to experimental animals. Administration of TNF and IL-1 in high doses induces hypotension, metabolic acidosis and multiple end-organ damage similar to that observed in endotoxin-induced shock.
Similar responses are also observed in acute inflammatory reactions in humans, particularly when the stimulatory signal required to initiate the inflammatory reaction is sufficiently large. Intense inflammatory responses to invasive organisms can cause tissue injury and patient mortality.
Acute inflammatory reactions are often initiated by invasive organisms and injury; however, there are many other disease states characterized by acute inflammation.
It is with this in mind that physicians attempt to control the acute inflammatory reaction with glucocorticoids, nonsteroidal anti-inflammatory agents and cytotoxic drugs. These general immunosuppressive agents are helpful but are not specifically directed to the resolution of the acute inflammatory response. Agents specifically directed to the control of the acute reaction would be less likely to promote the systemic side effects produced by general immunosuppressives and would permit better control over a potentially life-threatening reaction. Inhibitors of acute inflammation with fewer side effects would therefore be most useful.
The role of TGF.beta. (Transforming growth factor-beta) in acute inflammation has not been defined. TGF.beta. is present in a variety of cell types including activated macrophages. It is known that TGF.beta. can have both growth stimulatory and inhibitory activities on cell proliferation. TGF.beta. is also a potent immunosuppressive factor. It is present in rheumatoid synovial fluids and can inhibit IL-1 induced lymphocyte proliferation. Additionally, TGF.beta. can suppress production of TNF.alpha. from LPS-stimulated macrophages.
U.S. Pat. Nos. 4,806,523 and 4,971,952 teach the use of TGF.beta. to treat inflammation reactions such as those resulting from viral, bacteria fungal or autoimmune processes. As shown in the laboratory and in the experimental results disclosed herein, TGF.beta. is helpful but not always sufficient to control acute inflammatory reactions. Therefore, substances that could work alone or together with TGF.beta. to downregulate the inflammatory reaction would provide a more effective anti-inflammatory therapy.
Interleukin-6 (IL-6) is a cytokine that is known to induce terminal differentiation in B cells, stimulate T cell proliferation and induce the differentiation of hemopoietic stem cells. IL-6 is produced in a variety of cells including fibroblasts and monocytes. Intravenous IL-6 was reported to decrease intravenous endotoxin induced serum TNF levels in mice (Aderka et al. J. Immunol. 143:3517. 1989) and in rats (Ulich et al.; J. Immunol. (in press)). However, IL-6 is also reported to induce acute phase inflammatory responses (Castell et al.; Eur. J. Biochem 177:357-361 1988). I1-6 is known to have immuno-modulating activity, but its precise behavior in acute inflammation is not known.
The control of the acute inflammatory reaction can present significant problems to physicians. General immunosuppressive agents may not sufficiently control the acute reaction and may further hinder the resolution of the initial causative insult. The suppression of wound repair and decreased clearance of adventitious agents are two potential side effects of generalized immunosuppression.
It is an object of the invention to provide a method for controlling inflammation, and particularly for controlling the acute inflammatory reaction.
It is a further object of the invention to provide a method and composition that is nonsteroidal, and that is more effective than TGF.beta. alone.
These and other objects and advantages of the present invention will be apparent in the detailed description of the invention that follows.